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  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07F9/653—Five-membered rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
  • C07F9/32—Esters thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6596—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having atoms other than oxygen, sulfur, selenium, tellurium, nitrogen or phosphorus as ring hetero atoms

Definitions

• the present invention relates to new phosphinic amino acid compounds, to a process for their preparation and to pharmaceutical compositions containing them.
• the new phosphinic amino acid compounds according to the invention have the remarkable property of simultaneously inhibiting angiotensin I converting enzyme (ACE) and endothelin converting enzyme (ECE).
• ACE angiotensin I converting enzyme
• ECE endothelin converting enzyme
• vasoactive peptides vasoactive peptides
• vasoconstrictors angiotensin II, endothelin-1
• vasodilators natriuretic factors, bradykinin
• Angiotensin II is a vasoconstrictor and antinatriuretic octapeptide.
• the endothelins are vasoconstrictor and antinatriuretic polypeptides of about twenty amino acids containing two disulphide bridges linking cysteine residues.
• Bradykinin is a vasodilator and natriuretic nonapeptide.
• Angiotensin II, endothelin and bradykinin are the most important polypeptides hitherto considered to be involved in regulating vascular tone, cardiovascular remodelling and hydroelectrolytic homeostasis. Their metabolism is essentially controlled by the three enzymes ACE, ECE and NEP.
• ACE, ECE and NEP accordingly appear to be promising targets for the treatment of cardiovascular diseases. Therefore, in order to combat the adverse vasoconstrictor effects of angiotensin II and of endothelin-1 and to promote the protective vasodilator effects of ANP and of bradykinin, ACE, NEP and ECE inhibitors have been developed.
• ACE/NEP inhibitors (“vasopeptidase inhibitor” class) have also been synthesised and clinically tested.
• phosphinic acid compounds having a mixed ACE/NEP inhibitory activity useful in the treatment of cardiovascular diseases.
• the formulae of those compounds include:
• the interest in having mixed ECE/NEP inhibitors is to reduce the level of endothelin whilst increasing the level of natriuretic peptides and accordingly to obtain an additive or synergistic effect which is beneficial for the treatment of cardiovascular and renal diseases.
• NEP is one of the most important players in the degradation of bradykinin in vivo
• the clinical stop put on ACE/NEP inhibitors has also clearly invalidated the development of other multiple inhibitors of vasopeptidases including combining inhibition of NEP, namely mixed ECE/NEP or triple ECE/ACE/NEP inhibitors.
• the present invention has the aim of providing new compounds which behave as mixed ACE/ECE inhibitors without exerting any inhibition on NEP.
• the compounds of the present invention are accordingly very effective in the treatment of arterial hypertension and complications thereof including pulmonary arterial hypertension, myocardial ischaemia, angina pectoris, cardiac insufficiency, vasculopathies, nephropathies, diabetic retinopathies, atherosclerosis and post-angioplasty restenosis, acute or chronic renal insufficiency, cerebrovascular diseases including stroke and subarachnoid haemorrhage, and peripheral ischaemia.
• preferred compounds are compounds wherein R 1 and R 2 each represent a hydrogen atom.
• preferred compounds are compounds wherein R 1 represents a hydrogen atom and R 3 represents a phenyl group substituted by a hydroxy group.
• preferred compounds are compounds wherein R 2 represents a hydrogen atom and R 3 represents a phenyl group substituted by a hydroxy group.
• the present invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used, as starting material, diphenylmethanamine chloride, which is reacted with phenylacetaldehyde in the presence of phosphinic acid, H 3 PO 2 , and hydrochloric acid to yield the compound of formula (II):
• PG A is as defined hereinbefore and PG B represents a protecting group for the amine function (T. W. Greene, “ Protective Group in Organic Synthesis” , Wiley-Interscience, New-York, 1981) well known to the person skilled in the art, which compound of formula (XXI) is reacted:
• the present invention relates also to pharmaceutical compositions comprising compounds of formula (I) in combination with one or more pharmaceutically acceptable excipients.
• compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration, and especially tablets or dragées, sublingual tablets, sachets, paquets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and injectable or drinkable ampoules.
• the useful dose varies according to the sex, age and weight of the patient, the administration route, the nature of the therapeutic indication and any associated treatments and ranges from 0.1 mg to 1 g per 24 hours, in one or more administrations.
• the starting materials used are commercial products or are prepared according to known methods of preparation.
• a (5R,8*,11S) compound is understood to mean a racemic mixture of 2 diastereoisomers having the absolute configurations (5R,8S,11S) and (5R,8R,11S).
• the oil obtained is taken up in 100 ml of absolute ethanol and then a solution of KOH (12.2 g in 340 ml of ethanol) is added dropwise. After stirring at ambient temperature for 1.5 hours, the ethanol is evaporated off under reduced pressure, and the residue is dissolved in water and extracted with diethyl ether. The aqueous phase is cooled with the aid of an ice bath, acidified with 2M HCl to pH ⁇ 1 and extracted with diethyl ether. The organic phase is dried over sodium sulphate, filtered and then evaporated under reduced pressure.
• Step D (1R)-1- ⁇ [(Benzyloxy)carbonyl]amino ⁇ -2-phenylethylphosphinic acid
• Step E (1R)-1- ⁇ [(Benzyloxy)carbonyl]amino ⁇ -2-phenylethyl-[2-(ethoxycarbonyl)-4-pentynyl]phosphinic acid
• Step F 2- ⁇ [(1R)-1- ⁇ [(Benzyloxy)carbonyl]amino ⁇ -2-phenylethyl)(hydroxy)-phosphoryl]methyl ⁇ -4-pentynoic acid
• Step A 2- ⁇ [((1R)-1- ⁇ [(Benzyloxy)carbonyl]amino ⁇ -2-phenylethyl)(hydroxy)-phosphoryl]methyl ⁇ -4-pentynoic acid
• Step B 3-[((1R)-1- ⁇ [(Benzyloxy)carbonyl]amino ⁇ -2-phenylethyl)(hydroxy)-phosphoryl]-2-[(3-phenyl-5-isoxazolyl)methyl]propanoic acid
• 1,3-Dipolar cycloaddition is carried out on the compound of Step A above using benzaldehyde oxime, in accordance with a procedure described in the literature (A. Makaritis et al., Chem. Eur. J., 2003, 9, 2079-2094).
• Step A (1R)-1- ⁇ [(Benzyloxy)carbonyl]amino ⁇ -2-phenylethyl-[2-( ⁇ [(1S)-1-(1H-indol-3-ylmethyl)-2-methoxy-2-oxoethyl]amino ⁇ carbonyl)-4-pentynyl]phosphinic acid
• Step B (1R)-1- ⁇ [(Benzyloxy)carbonyl]amino ⁇ -2-phenylethyl- ⁇ 3- ⁇ [(1S)-1-(1H-indol-3-ylmethyl)-2-methoxy-2-oxoethyl]amino ⁇ -3-oxo-2-[(3-phenyl-4-isoxazolyl)methyl)]propyl ⁇ phosphinic acid
• Step C (5R,8*,11S)-5-Benzyl-6-hydroxy-11-(1H-indol-3-ylmethyl)-3,9-dioxo-1-phenyl-8-[(3-phenyl-4-isoxazolyl)methlyl)]-2-oxa-4,10-diaza-6-phosphadodecan-12-oic acid 6-oxide
• Step D (5R,8R,11S)-5-Benzyl-6-hydroxy-11-(1H-indol-3-ylmethyl)-3,9-dioxo-1-phenyl-8-[(3-phenyl-4-isoxazolyl)methyl)]-2-oxa-4,10-diaza-6-phosphadodecan-12-oic acid 6-oxide
• the (R,R,S) diastereoisomer was obtained by purification of the compound of Step C above in isocratic mode with a buffer composed of 40% acetonitrile and 60% 83.3 mM ammonium formate at pH 6.4, using a 250 ⁇ 30 mm AIT column (stationary phase Kromasil C 18 beads of 5 ⁇ m, pores 100 ⁇ ).
• Step A 2-( ⁇ [(1S)-1-Benzyl-2-tert-butoxy-2-oxoethyl]amino ⁇ carbonyl)-4-pentynyl-((1R)-1- ⁇ [(benzyloxy)carbonyl]amino ⁇ -2-phenylethyl)-phosphinic acid
• This compound is obtained according to the procedure described in Step A of Example 1, using L-phenylalanine O-di-tert-butyl ester chloride instead of 1-tryptophan methyl ester chloride.
• Step B 3-( ⁇ [(1S)-1-Benzyl-2-tert-butoxy-2-oxoethyl]amino ⁇ -3-oxo-2-[(3-phenyl-5-isoxazolyl)methyl]propyl((1R)-1- ⁇ [(benzyloxy)carbonyl]amino ⁇ -2-phenyl-ethyl)-phosphinic acid
• This compound is obtained according to the procedure described in Step B of Example 1, using the compound of Step A above.
• the product is purified by chromatography on silica gel (chloroform/methanol/acetic acid: 7/0.3/0.3).
• Step C (5R,8*,11S)-5,11-Dibenzyl-6-hydroxy-3,9-dioxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2-oxa-4,10-diaza-6-phosphadodecan-12-oic acid 6-oxide
• the product is obtained by reacting the compound of Step B above with trifluoroacetic acid, triisopropylamine, dichloromethane and water in the proportions 85/2.5/10/2.5.
• Step D (5R,8R,11S)-5,11-Dibenzyl-6-hydroxy-3,9-dioxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2-oxa-4,10-diaza-6-phosphadodecan-12-oic acid 6-oxide
• the (R,R,S) diastereoisomer was obtained by purification of the compound of Step C above in isocratic mode using a semi-preparative 250 ⁇ 10 mm AIT column (stationary phase Kromasil C 18 beads of 10 ⁇ m, pores 100 ⁇ ). Isocratic elution under acid conditions: 52% acetonitrile; 0.1% trifluoroacetic acid.
• Step A (1R)-1- ⁇ [(Benzyloxy)carbonyl]amino ⁇ -2-phenylethyl-[2-( ⁇ [(1S)-2-tert-butoxy-1-(4-tert-butoxybenzyl)-2-oxoethyl]amino ⁇ carbonyl)-4-pentynyl]phosphinic acid
• This compound is obtained according to the procedure described in Step A of Example 1, using L-tyrosine O-di-tert-butyl ester chloride instead of 1-tryptophan methyl ester chloride.
• Step B (1R)-1- ⁇ [(Benzyloxy)carbonyl]amino ⁇ -2-phenylethyl- ⁇ 3- ⁇ [(1S)-2-tert-butoxy-1-(4-tert-butoxybenzyl)-2-oxoethlyl]amino ⁇ -3-oxo-2-[(3-phenyl-5-isoxazolyl)-methyl]propyl ⁇ phosphinic acid
• Step C (5R,8*,11S)-5-Benzyl-6-hydroxy-11-(4-hydroxybenzyl-3,9-dioxo-1-phenyl-8[(3-phenyl-5-isoxazolyl)methyl]-2-oxa-4,10-diaza-6-phosphadodecan-12-oic acid 6-oxide
• Step D (5R,8R,11S)-5-Benzyl-6-hydroxy-11-(4-hydroxybenzyl)-3,9-dioxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2-oxa-4,10-diaza-6-phosphadodecan-12-oic acid 6-oxide
• the (R,R,S) diastereoisomer was obtained by purification of the compound of Step C above in isocratic mode using a semi-preparative 250 ⁇ 10 mm AIT column (stationary phase Kromasil C 18 beads of 10 ⁇ m, pores 100 ⁇ ). Isocratic elution under acid conditions: 43% acetonitrile; 0.1% trifluoroacetic acid.
• Step A N-[(Benzyloxy)carbonyl]-4-[(tert-butoxycarbonyl)oxy]phenylalanine
• Potassium hydroxide is added to a solution of 10 mmol of N-[(benzyloxy)carbonyl]-4-hydroxyphenylalanine until a pH of 12 is reached.
• the reaction mixture is cooled in an ice bath, and 1.5 equivalents of Boc 2 O are added, and the mixture is then returned to ambient temperature whilst maintaining the pH of the solution at 12 by addition of solid potassium hydroxide.
• a further 0.5 of an equivalent of Boc 2 O is added.
• the mixture is then concentrated under reduced pressure and the aqueous phase is extracted with a mixture (1/1) of Et 2 O/petroleum ether.
• the aqueous phase is acidified in the cold state with 2M HCl until a pH of 1 is reached, and is then extracted twice with ethyl acetate. Chromatography (chloroform/methanol: 9.5/0.5) allows the expected product to be isolated.
• Step B [(2- ⁇ [(Benzyloxy)carbonyl]amino ⁇ -3- ⁇ 4-[(tert-butoxycarbonyl)oxy]phenyl ⁇ -propanoyl)oxy]methyl pivalate
• Step C [(2-Amino-3- ⁇ 4-[(tert-butoxycarbonyl)oxy]phenyl ⁇ propanoyl)oxy]methyl 2,2-dimethylpropanoate hydrochloride
• Step D (5R,8*,11S)-5-Benzyl-11- ⁇ 4-[(tert-butoxycarbonyl)oxy]benzyl ⁇ -3.9,12,16-tetraoxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2,13,15-trioxa-4,10-diaza-17,17-dimethyloctadecane-6-phosphinic acid
• Step E (5R,8*,11S)-5-Benzyl-11-(4-hydroxybenzyl)-3,9,12,16-tetraoxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2,13,15-trioxa-4,10-diaza-17,17-dimethyloctadecane-6-phosphinic acid
• Step A 2- ⁇ [(Benzyloxy)carbonyl]amino ⁇ -3- ⁇ 4-[(tert-butoxycarbonyl)oxy]phenyl ⁇ ethyl propanoate
• Step B 2-Amino-3- ⁇ 4-[(tert-butoxycarbonyl)oxy]phenyl ⁇ ethyl propanoate hydrochloride
• Step C (5R,8*,11S)-5-Benzyl-11- ⁇ 4-[(tert-butoxycarbonyl)oxy]benzyl ⁇ -3,9,12-trioxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2,13-dioxa-4,10-diaza-pentadecane-6-phosphinic acid
• Step D (5R,8*,11S)-5-Benzyl-11-(4-hydroxybenzyl)-3,9,12-trioxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2,13-dioxa-4,10-diaza-pentadecane-6-phosphinic acid
• Step A 2-(Benzoylsulphanyl)-3-(4-tert-butoxyphenyl)-2- ⁇ [(9H-fluoren-9-ylmethoxy)carbonyl]amino ⁇ ethyl propanoate
• Step B 2-(Benzoylsulphanyl)-2-amino-3-(4-tert-butoxyphenyl)ethyl propanoate
• Step C (5R,8*,11S)-5-Benzyl-11-(4-tert-butoxybenzyl)-3,9,12,17-tetraoxo-1,17-diphenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2,13-dioxa-4,10-diaza-16-thiaheptadecane-6-phosphinic acid
• Step D (5R,8*,11S)-5-Benzyl-11-(4-hydroxybenzyl)-3,9,12,17-tetraoxo-1,17-diphenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2,13-dioxa-4,10-diaza-16-thiaheptadecane-6-phosphinic acid
• Step A (5R,8*,11S)-5-Benzyl-11-(4-tert-butoxybenzyl)-3,9,12-trioxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2,13-dioxa-4,10-diaza-14,14-dimethylpentadecane-6-phosphinic acid
• the product is obtained in accordance with the procedure of Step D of Example 4, using the compound of Preparation 3 and HCl.HTyr(OBu t )OBu t .
• Step B tert-Butyl (5R,8*,11S)-5-benzyl-11-4-(tert-butoxybenzyl)-6-[2(ethanethioate)ethoxy]-3,9-dioxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2-oxa-4,10-diaza-6-phosphadodecan-12-oate 6-oxide
• Step C (5R,8*,11S)-5-Benzyl-11-4-(tert-butoxybenzyl)-6-[2(ethanethioate)ethoxy]-3,9-dioxo-1-phényl-8-[(3-phényl-5-isoxazolyl)methyl]-2-oxa-4,10-diaza-6-phosphadodecan-12-oic acid-6-oxide
• Step A Ethyl (5R,8*,11S)-5-benzyl-11- ⁇ 4-[(tert-butoxycarbonyl)oxy]benzyl ⁇ -6-ethoxy-3,9-dioxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2-oxa-4,10-diaza-6-phosphadodecan-12-oate 6-oxide
• Step B Ethyl (5R,8*,11S)-5-benzyl-6-ethoxy-11-(4-hydroxybenzyl)-3,9-dioxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2-oxa-4,10-diaza-6-phosphadodecan-12-oate 6-oxide
• Step A Ethyl (5R,8*,11S)-5-benzyl-11- ⁇ 4-[(tert-butoxycarbonyl)oxy]benzyl ⁇ -6-[2-methyl-1-(propionyloxy)propoxyl]-3,9-dioxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2-oxa-4,10-diaza-6-phosphadodecan-12-oate 6-oxide
• the product is obtained in accordance with the procedure of Step B of Example 7, using the compound of Step C of Example 5 and BrCH(CH(CH 3 ) 2 )OCOEt (M. Neuenschwander et al., Helv. Chim. acta, 1978, 61, 2047-2058).
• Step B Ethyl (5R,8*,11S)-5-benzyl-11-(4-hydroxybenzyl)-6-[2-methyl-1-(propionyloxy)propoxy]-3,9-dioxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2-oxa-4,10-diaza-6-phosphadodecan-12-oate 6-oxide
• Step A tert-Butyl (5R,8*,11S)-5-benzyl-11-(4-tert-butoxybenzyl)-6-[2-methyl-1-(propionyloxy)propoxy]-3,9-dioxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methyl]-2-oxa-4,10-diaza-6-phosphadodecan-12-oate 6-oxide
• Step B (5R,8*,11S)-5-Benzyl-11-(4-hydroxybenzyl)-6-[2-methyl-1-(propionyloxy)propoxy]-3,9-dioxo-1-phenyl-8-[(3-phenyl-5-isoxazolyl)methlyl]-2-oxa-4,10-diaza-6-phosphadodecan-12-oic acid 6-oxide
• ACE angiotensin converting enzyme
• ECE endothelin converting enzyme
• the tests were carried out in duplicate in 96-well plates.
• the inhibitor was incubated together with the enzyme for 45 minutes before the addition of a quenched-fluorescence substrate.
• the fluorescence emitted was detected and measured in a Fluoroscan Ascent plate reader (Thermo-Labsystems).
• the fluorogenic substrates used are: Mca-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Dpa COOH (5 ⁇ M) with ACE, and Mca-Arg-Pro-Pro-Gly-Phe-Ser-Ala-Phc-Lys(Dnp) COOH (5 ⁇ M; R&D Systems) with ECE.
• the compounds of the invention show good inhibition of ACE and of ECE, with IC 50 values of 25 nM and 8 nM respectively.
• composition 1000 tablets each comprising 5 mg of the 5 g compound of Example 1 wheat starch 20 g maize starch 20 g lactose 30 g magnesium stearate 2 g silica 1 g hydroxypropylcellulose 2 g

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• 2007
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